Masitinib demonstrates efficacy, safety in Alzheimer’s disease

 Is this going to be in your doctor's toolbox? Especially if their Alzheimer's prevention protocols didn't work or didn't exist.

You need to have plans to prevent this. Does your doctor?

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Masitinib demonstrates efficacy, safety in Alzheimer’s disease

Masitinib, an oral tyrosine kinase inhibitor, improved measures of cognition, memory and activities of daily living in a phase 2b/3 study of patients with mild and moderate Alzheimer’s disease, according to a press release.

Moreover, fewer patients who received masitnib progressed to a severe stage of dementia, according to the release. The drug demonstrated an acceptable safety profile, one that was consistent with the known tolerability of the agent.

Jeffrey L. Cummings

“The preliminary results from this study support efficacy on important outcomes assessing both cognition and function. The observed patient tolerability is encouraging,” Jeffrey L. Cummings, MD, director of the Chamber-Grundy Center for Transformative Neuroscience at University of Nevada, Las Vegas, said in the release. “Masitinib's mechanism is novel in its targeting of the innate immune system via mast cells and microglia. A growing body of evidence suggests that microglia play a central role in [AD] and other neurodegenerative disorders."

The phase 2b/3 ABO9004 study, an international, randomized, placebo-controlled trial, examined different doses of masitinib (4.5 mg/kg/day and a titrated dose from 4.5 to 6 mg/kg/day) in patients with confirmed mild to moderate AD. The researchers compared the efficacy and safety of masinitib with placebo following 24 weeks of treatment. They administered masitinib as an add-on to a cholinesterase inhibitor (donepezil, rivastigmine or galantamine) and/or memantine.

Masitinib 4.5 mg/kg per day, which was given to 182 patients, provided a significant treatment effect compared with the control arm (n = 176) regarding the primary endpoint of change from baseline in the AD Assessment Scale-Cognitive Subscale (P = .0003). Masitinib 4.5 mg/kg per day also resulted in a significant change from baseline on the AD Cooperative Study Activities of Daily Living score (P = .0381).

Significantly fewer patients treated with masitinib 4.5 mg/kg/day progressed to a severe stage of dementia after 24 weeks, according to the press release (P = .0446).

Bruno Dubois

“The fact that masitinib could significantly reduce the proportion of patients reaching the stage of severe dementia is particularly interesting because this stage of the disease represents a significant burden for the society,” Bruno Dubois, MD, PhD, professor of neurology at the Neurological Institute of Salpetriere University Hospital at Paris and coordinating investigator of the study, said in the release.

The study results demonstrated an acceptable safety profile for masitinib 4.5 mg/kg per day, one consistent with the known tolerability profile for this agent, according to the release. At least one adverse event occurred in 87% of patients in the masitinib arm compared with 77.5% of patients in the control arm. More patients in the masitinib arm (13%) experienced at least one serious, non-fatal adverse event compared with the control arm (5.4%). Researchers reported at least one severe adverse event in 26.5% of participants in the masitinib arm vs. 19.3% of participants in the control arm.

“There is a vacuum of treatment options for patients with [AD] and today very few attempts to address the population with confirmed mild or moderate dementia associated with [AD],” Dubois said. “These data are very encouraging and may provide new hope for patients with [AD].”

Reference:

AB Science. AB Science announces that phase 2B/3 study evaluating masitinib in Alzheimer’s disease met its primary endpoint. Available at: https://www.ab-science.com/positive-confirmatory-phase-2-3-study-ab09004-with-masitinib-in-alzheimers-disease/. Accessed Dec. 16, 2020.

Editor’s note: This story was updated on Thursday, Dec. 17, 2020, to reflect revised safety data.

 

Neuronal protein kinase signaling cascades and excitotoxic cell death

Even worse I bet your doctor and hospital have done nothing with this since it came out in June 2001. 

Neuronal protein kinase signaling cascades and excitotoxic cell death

 June 2001

Skaper SD¹, Facci L, Strijbos PJ.

Author information

Abstract

Perturbation of normal survival mechanisms may play a role in a large number of disease processes. Glutamate neurotoxicity, particularly when mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, has been hypothesized to underlie several types of acute brain injury, including stroke. Several neurological insults linked to excessive release of glutamate and neuronal death result in tyrosine kinase activation, including p44/42 mitogen activated protein (MAP) kinase. To further explore a role for MAP kinase activation in excitotoxicity, we used a novel tissue culture model to induce neurotoxicity. Removal of the endogenous blockade by Mg2+ of the NMDA receptor in cultured hippocampal neurons triggers a self perpetuating cycle of excitotoxicity, which has relatively slow onset, and is critically dependent on NMDA receptors and activation of voltage gated Na+ channels. These injury conditions led to a rapid phosphorylation of p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK inhibition was associated with protection against synaptically mediated excitotoxicity. Interestingly, hippocampal neurons preconditioned by a sublethal exposure to Mg(2+)-free conditions were rendered resistant to injury induced by a subsequently longer exposure to this insult; the preconditioning effect was MAP kinase dependent. The MAP kinase signaling pathway can also promote polypeptide growth factor mediated neuronal survival. MAP kinase regulated pathways may act to promote survival or death, depending upon the cellular context in which they are activated.

PMID:

11462762

[Indexed for MEDLINE]

How brain tissue recovers after injury - astrocytes

Your competent? doctor and hospital should be entering into collaboration with researchers to translate this into a useable stroke protocol for stroke recovery. But I bet followup never occurs because of the incompetency of your doctor and stroke hospital. 

How brain tissue recovers after injury - astrocytes

A research team led by Associate Professor Mitsuharu ENDO and Professor Yasuhiro MINAMI (both from the Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University) has pinpointed the mechanism underlying astrocyte-mediated restoration of brain tissue after an injury. This could lead to new treatments that encourage regeneration by limiting damage to neurons incurred by reduced blood supply or trauma. The findings were published on October 11 in the online version of Glia ahead of print release in January 2017.

When the brain is damaged by trauma or ischemia (restriction in blood supply), immune cells such as macrophages and lymphocytes dispose of the damaged neurons with an inflammatory response. However, an excessive inflammatory response can also harm healthy neurons.
Astrocytes are a type of glial cell, and the most numerous cell within the human cerebral cortex. In addition to their supportive role in providing nutrients to neurons, studies have shown that they have various other functions, including the direct or active regulation of neuronal activities.
It has recently become clear that astrocytes also have an important function in the restoration of injured brain tissue. While astrocytes do not normally proliferate in healthy brains, they start to proliferate and increase their numbers around injured areas and minimize inflammation by surrounding the damaged neurons, other astrocytes, and inflammatory cells that have entered the damaged zone. Until now the mechanism that prompts astrocytes to proliferate in response to injury was unclear.
The research team focused on the fact that the astrocytes which proliferate around injured areas acquire characteristics similar to neural stem cells. The receptor tyrosine kinase Ror2, a cell surface protein, is highly expressed in neural stem cells in the developing brain. Normally the Ror2 gene is "switched off" within adult brains, but these findings showed that when the brain was injured, Ror2 was expressed in a certain population of the astrocytes around the injured area.
Ror2 is an important cell-surface protein that regulates the proliferation of neural stem cells, so the researchers proposed that Ror2 was regulating the proliferation of astrocytes around the injured areas. They tested this using model mice for which the Ror2 gene did not express in astrocytes. In these mice, the number of proliferating astrocytes after injury showed a remarkable decrease, and the density of astrocytes around the injury site was reduced. Using cultured astrocytes, the team analyzed the mechanism for activating the Ror2 gene, and ascertained that basic fibroblast growth factor (bFGF) can "switch on" Ror2 in some astrocytes.
This research showed that in injured brains, the astrocytes that show (high) expression of Ror2 induced by bFGF signal are primarily responsible for starting proliferation. bFGF is produced by different cell types, including neurons and astrocytes in the injury zone that have escaped damage. Among the astrocytes that received these bFGF signals around the injury zone, some express Ror2 and some do not. The fact that proliferating astrocytes after brain injury are reduced during aging raises the possibility that the population of astrocytes that can express Ror2 might decrease during aging, which could cause an increase in senile dementia. Researchers are aiming to clarify the mechanism that creates these different cell populations of astrocytes.
By artificially controlling the proliferation of astrocytes, in the future we can potentially minimize damage caused to neurons by brain injuries and establish a new treatment that encourages regeneration of damaged brain areas.

Figure: diagram of the research findings (Taken from article's Table of Contents Image) bFGF is produced in the injured zone of the cerebral cortex. Ror2 expression is induced in some population of the astrocytes that receive the bFGF signal, restarting their proliferation by accelerating the progression of their cell cycle. Credit: Kobe University

More information: Mitsuharu Endo et al, Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury, Glia (2017). DOI: 10.1002/glia.23086
Provided by: Kobe University

Drug Targeting Blood-Brain Barrier 'Hopeful' in Stroke

Would this be a possible solution to  Inflammatory action leaking through the blood brain barrier. in the neuronal cascade of death? More research needed that will never occur. 

Drug Targeting Blood-Brain Barrier 'Hopeful' in Stroke

A possible new treatment for acute ischemic stroke targeting the blood-brain barrier has shown promising results in an early randomized clinical trial.
The drug, imatinib, is a tyrosine kinase inhibitor already available for the treatment of certain cancers.
Initial results in stroke were presented at the recent European Stroke Organisation Conference (ESOC) 2016 by Nils Wahlgren, MD, Karolinska Institute, Stockholm, Sweden.
"We believe our results open up an opportunity for a novel third treatment for acute ischemic stroke to complement thrombolysis and thrombectomy," he concluded.
Professor Wahlgren explained that in experimental models, imatinib has preserved the integrity of the blood-brain barrier, which opens up during ischemic stroke, allowing an influx of inflammatory cells into the brain, and contributes to edema, hemorrhagic transformation, and increased mortality. This effect can be made worse by the use of tissue plasminogen activator (tPA).
"This preliminary randomized study suggested that imatinib is safe and generally well tolerated in ischemic stroke patients treated with IV [intravenous] tPA. The high dose increased neurological scores, and there was a suggestion of improved functional independence and reduced risk of hemorrhagic transformation," Professor Wahlgren stated.
"The effect may be mediated by restoring the integrity of the blood-brain barrier, which can lead to reduced edema and subsequent inflammatory responses," he added.
Commenting for Medscape Medical News, president of the European Stroke Organisation, Valeria Caso, MD, University of Perugia, Italy, said the study was very hopeful.
"These are excellent results in this initial early study. We need to now see what happens in larger trials.
"We have been trying to find agents that improve the efficiency of thrombolysis for many years," she added. "Many neuroprotective drugs have been tried without success, but this agent acts differently — targeting the blood-brain barrier — so it is something novel and it really does look like it could be a light at the end of the tunnel."
I-STROKE
The current study — known as I-STROKE — was conducted to clarify whether imatinib is safe and tolerable in an acute ischemic stroke population and whether there is any indication of reduced hemorrhage and edema and improved neurologic function.
The study involved 60 patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 7 or greater who received tPA within 4.5 hours of symptom onset. They were randomly assigned to one of three doses of imatinib (15 patients each to 400 mg, 600 mg, or 800 mg daily) or no additional treatment (controls) within 1 hour of completion of reperfusion therapy.
Results showed no serious treatment-related adverse events but a few mild reversible effects, such as itching, skin reactions, and nausea and vomiting.
In terms of efficacy, there were 28 hemorrhagic transformations in the study, with no overall difference between the imatinib patients and controls. "However, interestingly there were no transformations at all in the high-dose imatinib group, who were treated within 5 hours of symptom onset," Professor Wahlgren reported.
In terms of neurologic outcomes, there was an improvement in NIHSS scores (from baseline to 90 days) in the control group and then a dose-related stepwise further improvement in imatinib-treated patients, with the highest dose showing the best effect and a significant benefit shown over the control group.

The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction

More research needed. Don't know who to tell you to call to accomplish more human research because stroke has NO leadership or strategy. 

The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction

1. Judith M.M. van Eeuwijk*,
2. David Stegner*,
3. David J. Lamb,
4. Peter Kraft,
5. Sarah Beck,
6. Ina Thielmann,
7. Friedemann Kiefer,
8. Barbara Walzog,
9. Guido Stoll,
10. Bernhard Nieswandt

+ Author Affiliations

1. From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).

1. Correspondence to Bernhard Nieswandt, PhD, Department of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Str. 2/D15, Würzburg 97078, Germany. E-mail bernhard.nieswandt@virchow.uni-wuerzburg.de

1. ↵* These authors contributed equally to this article.

Abstract

Objective—Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI (GPVI) is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors. We sought to assess whether Syk might be an effective antithrombotic target.

Approach and Results—We demonstrate that mice lacking Syk in platelets specifically are protected from arterial thrombus formation and ischemic stroke but display unaltered hemostasis. Furthermore, we show that mice treated with the novel, selective, and orally bioavailable Syk inhibitor BI1002494 were protected in a model of arterial thrombosis and had smaller infarct sizes and a significantly better neurological outcome 24 hours after transient middle cerebral artery occlusion, also when BI1002494 was administered therapeutically, that is, after ischemia.

Conclusions—These results provide direct evidence that pharmacological Syk inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and to limit infarct progression in acute stroke.

TSRI scientists map out protein structure involved in cellular function, nervous system development

How much of this protein structure is needed because we are now redeveloping our nervous system? Does your doctor have ANY clue about this need? 

TSRI scientists map out protein structure involved in cellular function, nervous system development

Scientists from The Scripps Research Institute (TSRI), working closely with researchers at the National Institutes of Health (NIH), have mapped out the structure of an important protein involved in cellular function and nervous system development.
The new structure provides crucial information for understanding how the protein binds to cellular components. It's also the first structure determined of any ligase in the tubulin tyrosine ligase-like (TTLL) family.
Scientists have been especially curious about the role of TTLLs because mutations in these proteins have been linked to a range of neurodegenerative diseases, including retinal dystrophy and the rare Joubert syndrome.
"This protein is highly expressed in the nervous system and has an integral role in neuronal development," said Elizabeth Wilson-Kubalek, senior staff scientist in Professor Ron Milligan's laboratory at TSRI and co-first author of the new paper with Christopher Garnham and Annapurna Vemu of the NIH's National Institute of Neurological Disorders and Stroke (NINDS).
The new research was published online ahead of print by the journal Cell.
More at link.

Source:

http://www.scripps.edu/

New Mexico startup looks to bring to market a drug to stop brain injury during stroke

Well it's about time, with the efficacy rate of tPA at only 12%  for full recovery!

Who is looking into the other causes of neuronal death? Does your doctor even know about them?
1.  Excitotoxicity
2.  Glutamate poisoning
3.  Capillaries that don't open due to pericytes
4.  Inflammatory action leaking through the blood brain barrier
5. Lysosomal Membrane Permeabilization as a Key Player in Brain Ischemic Cell Death.
6.   Reperfusion injury
New drug here: 

New Mexico startup looks to bring to market a drug to stop brain injury during stroke  

One of the most challenging things about the gold standard for stroke treatment, the drug tPA, is that to most effectively prevent long-term brain damage, it has to be given within three hours of stroke onset.
A New Mexico drug startup called Zocere isn’t trying to replace tPA, but rather to act as a protector to neurons in the brain during stroke.
“We see an opportunity for a vial of our product to sit on an ambulance or in an emergency room to protect he neurons until treatment can be given,” said Wayne Laslie, president and CEO of Zocere.
Between 80 and 90 percent of strokes are caused by blood clots that interrupt blood flow to the brain. tPA, the only FDA-approved drug for stroke, dissolves that clot and restores bloodflow to the brain. But it’s used cautiously by medical professionals, as breaking down clots can cause damaging bleeding into the brain.

Zocere’s goal is to protect neurons from both potential sources of injury – from oxygen and glucose deprivation caused by the clot and from rapid reperfusion when that clot breaks up.
The injectable ­drug it’s developing is a derivative of a naturally occurring enzyme in the brain called tyrosine phosphatase and acts on a pathway called NMDAR. Overactivation of NMDA receptors is known to be a key contributor of brain damage following a stroke.
While many other researchers in the past have attempted to block the pathway, none have been able to do so effectively and without significant side effects, Laslie said.
“Our drug works far downstream in that pathway, and we speculate there should be fewer side effects,” he said.
In rodent models of ischemic stroke, it’s demonstrated the ability to cross the blood-brain barrier and reduce brain damage, according to Laslie.
Laslie has spent time in various leadership roles at Myriad Pharmaceuticals (now Myrexis) and Pfizer, and was brought in to Zocere, formerly known as Tyrosine Pharma, to put a pre-clinical development plan in place. Now that that’s complete and the company has secured rights to develop the drug from the University of New Mexico, the company is moving toward IND-enabling studies.
Founded in early 2013, Zocere is developing a peptide discovered by Dr. Surojit Paul at UNM. Paul scored a $1.6 million NIH grant, and Zocere later added funding by raising $500,000 from the New Mexico Angels. Laslie said he’ll be reaching out to other funding groups and potential partners to help the company get through preclinical studies.
In the spectrum of technologies in the pipeline for stroke diagnosis and treatment, Zocere’s falls at the early treatment stage. Other approaches to treatment being developed right now include devices to get tPA to the brain quicker and stem cell techniques to repair or replace damaged cells.
Stroke is the second-leading cause of death worldwide and a common cause of long-term disability.

Read more: http://medcitynews.com/2014/03/protect-neurons-stroke/#ixzz2vwZBDnCj

Dietary Tyrosine/Phenylalanine Depletion Effects on Behavioral And Brain Signatures of Human Motivational Processing

I 'm sure your doctor wants to make sure you are motivated to get to 100% recovery. And they'll do anything to get you there including reading research like this. (snort,snort) 

Dietary Tyrosine/Phenylalanine Depletion Effects on Behavioral And Brain Signatures of Human Motivational Processing

(PMID:23995581)

• Abstract
• Citations
• BioEntities
• Related Articles
• External Links

Bjork JM, Grant SJ, Chen G, Hommer DW

Division of Clinical Neuroscience and Behavioral Research, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA.

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology [2013]

Type: Journal Article

Abstract

Highlight Terms Gene Ontology(2) Diseases(1) Chemicals(2)

Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: 1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and 2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.Neuropsychopharmacology accepted article preview online, 2 September 2013. doi:10.1038/npp.2013.232.

Discovery of 'executioner' protein opens door to new options for stroke ALS, spinal cord injury

So ask your researchers to go back over the 1000 failed hyperacute therapies and see if  this new knowledge could require new clinical trials.
Discovery of 'executioner' protein opens door to new options for stroke ALS, spinal cord injury

Oxidative stress turns a protein that normally protects healthy cells into their executioner, according to a study released today in the Proceedings of the National Academy of Sciences journal.
Alvaro Estevez, an associate professor at the University of Central Florida's College of Medicine, led the multi-university team that made the discovery, which could eventually help scientists develop new therapies to combat a host of conditions from stroke to Lou Gehrig's disease
Researchers have long known that oxidative stress damages cells and results in neurodegeneration, inflammation and aging. It was commonly believed that oxidation made a "crude," demolition-like attack on cells, causing them to crumble like a building in an earthquake, Estevez said. However, the latest findings show that oxidation results in a much more targeted attack to specific parts of the cell. Oxidative stress damages a specific "chaperone" cell protein called Hsp90. It plays a role in up to 200 different cell functions. But when a form of oxidative stress called tyrosine nitration modifies that protein, it turns into the cell "executioner" shutting it down.
"The concept that a protein that is normally protective and indispensable for cell survival and growth can turn into a killing machine, and just because of one specific oxidative modification, is amazing," said Maria C. Franco, a postdoctoral associate at UCF's Burnett School of Biomedical Sciences. She co-wrote the study. "Considering that this modified protein is present in a vast number of pathologies, it gives us hopes on finding new therapeutics approaches for several different diseases."
For example, researchers could devise a drug that stroke patients could take at the onset of their symptoms to prevent more healthy cells from dying, thus limiting the damage of the stroke. Because oxidation is linked to inflammation, researchers believe tyrosine nitration could also be related to other health problems including heart disease, cancer, aging and chronic pain.
"These are very exciting results and could begin a major shift in medicine," said Joseph Beckman, from Oregon State University Environmental Health Sciences Center, a collaborator on the study. "Preventing this process of tyrosine nitration may protect against a wide range of degenerative diseases."
"Most people think of things like heart disease, cancer, aging, liver disease, even the damage from spinal injury as completely different medical issues," Beckman said. "To the extent they can often be traced back to inflammatory processes that are caused by oxidative attack and cellular damage, they can be more similar than different. It could be possible to develop therapies with value against many seemingly different health problems."